Derivatives of 2-nitrobenzofuran

ABSTRACT

Compounds wherein 2-nitrobenzofuran is substituted by one or two phenyl groups and certain other substituents which are active as antimicrobial agents, processes for their use and intermediates therefor.

BACKGROUND OF THE INVENTION

This is a division of copending application Ser. No. 13,543 filed Feb.21, 1979, now U.S. Pat. No. 4,208,337, Ser. No. 13,543 being a divisionof copending application Ser. No. 620,140 filed Dec. 19, 1977 (now U.S.Pat. No. 4,153,721).

This invention relates to a class of 2-nitrobenzofuran derivativeswherein the 3-position is substituted by a methyl, ethyl or phenylgroup, the benzo ring is substituted by a phenyl group, and oneadditional substituent selected from carboxyl, hydroxymethyl,hydroxyethyl, carboxymethyl and ureidomethyl is present, andpharmaceutically acceptable salts of the acids. It also relates to theuse of the compounds as antimicrobial agents and to syntheticintermediates useful for the preparation of the compounds of theinvention.

Compounds wherein 2-nitro-3-phenylbenzofuran is substituted by acarboxyl group or an alkanoic acid group are known to have antimicrobialactivity (see Belgian Pat. No. 846,502 and German OffenlegungsschriftNo. P 2642877). The compounds of the present invention which containsuch groups differ from these prior art compounds in that theyadditionally have a phenyl group bonded to the benzo ring. The prior artdoes not disclose compounds which are structurally similar to theremaining compounds of the invention (i.e. which do not contain acarboxyl group or an alkanoic acid group).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to 3-substituted-(4,5,6 or7-phenyl)-2-nitrobenzofurans substituted by carboxy (--COOH),carboxymethyl (--CH₂ COOH), hydroxymethyl (--CH₂ OH), hydroxyethyl(--CH₂ CH₂ OH) or ureidomethyl ##STR1## groups and to chlorides andsimple alkyl esters and salts of the acids. It also relates to use ofthe compounds as antimicrobial agents and to synthetic intermediatesuseful for the preparation of the compounds of the invention.

According to the present invention there is provided a class ofcompounds of the formula ##STR2## wherein R is hydrogen, carboxyl,carboxymethyl, hydroxymethyl, hydroxyethyl or ureidomethyl,

X is hydrogen or carboxyl and

Y is methyl, ethyl, phenyl or carboxyphenyl

provided that the compound contains one and only one group selected fromcarboxyl, carboxymethyl, hydroxymethyl, hydroxyethyl or ureidomethyl andprovided further that when R is carboxymethyl, Y is methyl or ethyl,and, when an acid group is present, acid chlorides, lower alkyl estersand pharmaceutically acceptable salts thereof (in which the lower alkylgroup of the ester contains one to four carbon atoms).

The compounds of the invention are ordinarily white or yellow solidswhen purified. They are substantially insoluble in water or aliphatichydrocarbons, and are more soluble in lower alcohols, halogenatedsolvents, benzene, N,N-dimethylformamide and the like. The alkali metalsalts of acids of the invention have appreciable solubility in water andlower alkanols.

All of the compounds of the invention are active against bacteria andsome are also active against other microorganisms, including fungi andprotozoa, in vitro and topically. Thus, they can be used fordisinfecting and sterilizing, for example of medical and dentalequipment, as components of disinfecting solutions. The compounds areparticularly useful as antibacterial agents. In general, the compoundsare also active in vivo in animal tests. For applications in which watersolubility is of importance, the salts of acids of the invention may beused.

The compounds of the invention in which X is hydrogen form a preferredsubclass. Another preferred subclass is comprised of the compounds ofthe invention in which Y is phenyl. The alkali metal, alkaline earth,aluminum, iron and other metal and amine salts are often the equivalentsof the corresponding acid-form compounds, and offer advantages insolubility, absorption, persistence, formulation and the like. The saltsare of particular interest for topical uses (e.g. ophthalmic anddermtologic). The alkali metal salts (e.g. sodium and potassium) arepreferred.

The final compounds of the invention are prepared by several methods(often requiring multiple-step reactions). Thus, the compounds wherein Yis carboxyphenyl (and X and R are therefore necessarily hydrogen) orwherein one of X and R is carboxyl (and Y is necessarily phenyl and theother of X and R is carboxyl (and Y is necessarily phenyl and the otherof X and R is necessarily hydrogen) are prepared by starting with anα-bromoacetophenone and a hydroxybiphenyl according to the followingreaction scheme: ##STR3## wherein one of the Q groups in each compoundII-III is bromine and two are hydrogen, one of the W groups in IV iscyano and two are hydrogen, and one of the V groups in each compound Vand VI is carboxyl and two are hydrogen.

The reaction to prepare the novel intermediate condensation products offormula II is generally carried out at reflux in an inert solvent suchas benzene, acetone and the like and in the presence of a weak base suchas sodium or potassium carbonate. Increased basicity may be used toincrease the rate of reaction, if desired. The condensates II arecyclized by heating in the presence of polyphosphoric acid to form thecompounds III which are, in turn, reacted with a metal cyanide,preferably cuprous cyanide, in a basic organic solvent such as pyridineor quinoline at elevated temperatures of 100°-250° C. to form theproducts IV. These are converted to the corresponding carboxylic acids Vby hydrolysis under basic or acidic conditions.

The compounds of formula V are converted to the desired 2-nitrocompounds of formula VI (which fall within the class of compoundscovered by formula I) either by direct nitration or by halogendisplacement (i.e. specifically halogenating the 2-position of thebenzofuran group of the compound V, then replacing the 2-halogen atomwith a nitro group employing a nitrating reagent).

The direct nitration can be carried out with fuming nitric acid inacetic acid or acetic anhydride or with dinitrogen tetraoxide in aninert solvent such as dichloromethane. In order to avoid aromaticnitration moderate temperatures of 0° to 30° C. are generally used.

The halogenation step of the second process may be bromination oriodination. The bromation can be carried out using N-bromosuccinimide orpreferably bromine in a suitable solvent such as dichloromethane oracetic acid. Bromination is carried out under mild conditions, e.g. 0°to 30° C. to avoid aromatic bromination. The bromo compound may beisolated or used without isolation. Isolation may be carried out byextraction, precipitation by the addition of a non-solvent such aswater, evaporation of volatile reaction components, etc. The iodinationis carried out e.g. with a molecular iodine in the presence of yellowmercuric oxide in an inert solvent such as benzene. Generally thesereactions are carried out at about 25° to 125° C., for example at thereflux temperture of the solvent.

In the final step of the halogen displacement process, the 2-halosubstituent can be displaced by means of selective nitrating agents,such as strong nitric acid solution, for example 70 percent aqueousnitric acid, dinitrogen tetraoxide in e.g. acetic acid ordichloromethane solution or a mixture of sodium nitrite and a strongacid. When 70 percent nitric acid is used as the nitrating reagent for2-halo derivatives, preferably about two or three moles each of sodiumnitrite and nitric acid per mole of benzofuran is included. About fourto twenty milliliters of acetic acid per gram of 2-halobenzofuranderivative is used, depending on its solubility. It is desired tomaintain the dissolution of the 2-halobenzofuran derivative, and theamount of acetic acid and the reaction temperature is adjusted toachieve this result readily. The reaction temperature is about 25° to100° C., and preferably about 60° to 80° C. when the halogen is bromine.

It has been found that a mixture of sodium nitrite, sulfuric acid andacetic acid will also nitrate the 2-halobenzofuran derivativessuccessfully in the 2-position. The 2-halobenzofuran derivative isdissolved in acetic acid to maintain solution (up to 20 ml. per gramrequired), and concentrated sulfuric acid is added, from two to tenmilliliters per gram of benzofuran. Sodium nitrite is then added to thesolution. The reaction temperature is about 20° to 100° C., andpreferably about 55° C. The sodium nitrite can be replaced in thisreaction by other metal nitrites such as potassium nitrite. In each ofthe preceding nitration methods, polynitration is a side-reaction.

A combination of dinitrogen tetroxide in an inert solvent in thepresence of an alkene is one presently preferred nitration methodaccording to the halogen displacement process, with acetic acid anddichloromethane as the preferred solvents. For example, two to fiveliters of acetic acid per mole of benzofuran or halobenzofuranderivatives are generally used. At least one mole of dinitrogentetraoxide per mole of benzofuran is used. The exact amount depends onthe rate of reaction desired, the extent of volatilization and otherphysical losses and the amount of competitive addition to the addedolefin. An alkene is preferably used with a 2-bromobenzofuranintermediate to remove the elements of BrNO₂ and minimize bromination asa side reaction. Cyclohexene is satisfactory for this use. Preferablyequimolar amounts of alkene and dinitrogen tetraoxide are used. Theolefin is chosen to be less reactive to N₂ O₄ than the benzofuran butmore reactive to BrNO₂ than the benzofuran. An acidic olefin, e.g.3-cyclohexene carboxylic acid, is advantageous when the nitrated productis neutral. The temperature of these reactions is generally about 0° to80° C., preferably 20° to 45° C. for bromine exchange and about 0° to25° C. for iodine exchange and direct nitration. When 2-iodobenzofuransare used, the olefin is not required (since the iodine is generallyunreactive to the benzofuran under the reaction conditions) and onlyone-half mole of N₂ O₄ is theoretically then required.

The compounds of formula I in which R is hydroxymethyl or hydroxyethylare prepared by reduction of the corresponding carboxylic acids oracetic acids or their esters. The preparation of the carboxylic acidsand the acetic acids, except for those acetic acids in which Y is phenylor substituted phenyl, are described elsewhere herein. The acetic acidintermediates in which Y is phenyl or substituted phenyl are prepared asfollows:

(Hydroxyphenyl)phenylacetic acids are reacted by known methods withoptionally substituted α-bromoacetophenones to provide compounds of theformula. ##STR4## These compounds are cyclized by heating at about 50°to 100° C. in polyphosphoric acid. Simple basic hydrolysis of the estersprovides compounds of the formula ##STR5## which are the desired aceticacid intermediates.

The reductions to prepare the hydroxymethyl and hydroxyethyl compoundsof the present invention are carried out using hydride reducing agentssuch as sodium borohydride, lithium aluminum hyride or borane. Thereductions can be carried out on suitable reactants either before orafter the benzofuran ring has been substituted by the 2-nitro group.Such reactions are carried out in suitable non-reactive solvents knownto those skilled in the art such as diethyl ether, toluene,tetrahydrofuran and the like. Reaction temperatures are generally up tothe reflux temperature of the reaction solvent. Cooling may be necessaryto maintain control of the rate of reaction.

The compounds of the invention wherein R is a ureidomethyl group areprepared in several steps from the corresponding acetic acid-substitutedcompounds. The acids are first converted to the corresponding acidchlorides by conventional methods, such as reaction with thionylchloride or oxalyl chloride, followed by reaction with sodium azide andconversion to the isocyanate by heating in toluene. Finally, theisocyanate is reacted with ammonia or the appropriate amines to providethe ureidomethyl-substituted or the N-substituted or N,N-disubstitutedureidomethyl-substituted compounds.

The latter reaction is carried out in an inert solvent such asdichloromethane, preferably at temperatures of -20° to 30° C. tomaintain control of the reaction. If it is necessary to increase thereaction rate, temperatures up to the reflux temperature of the reactionmixture are used.

Compounds of the invention wherein R is --CH₂ CO₂ H and Y is methyl orethyl are prepared starting with the corresponding(hydroxyphenyl)phenylacetic acid and α-halomethyl methyl ketone,α-halomethyl ethyl ketone or e.g. α-chloroacetoacetate followed byhydrolysis and decarboxylation according to the following reactionscheme: ##STR6## wherein Z is hydrogen or alkyl of one to four carbonatoms, A is methyl or ethyl and B is hydrogen or ethyl carboxylate. Theintermediate compounds VII, VIII and IX are novel and form separateaspects of the present invention. The reaction to form the compounds VIIis generally run at reflux, in an inert solvent in the presence of abase such as sodium carbonate or, when ethyl α-chloroacetoacetate isused, the preferred base is sodium ethoxide.

The cyclization in polyphosphoric acid or sulfuric acid of compounds offormula VII gives compounds of formula VIII. When B is ethylcarboxylate, hydrolysis and decarboxylation give compounds of theformula IX (wherein B and Z are hydrogen).

The compounds IX are converted to the corresponding 2-nitro compounds offormula I either by direct nitration or by preparing the corresponding2-halo compound then replacing the halogen with a nitro group employinga nitrating agent, as previously described. The novel intermediate2-iodo and 2-bromo compounds, which are also novel, are prepared byiodination (e.g. in the presence of mercuric oxide) or bromination, bothin an inert solvent.

The pharmaceutically acceptable salts of the invention are readilyprepared by reaction of the corresponding free acids with theappropriate base and optionally in a suitable solvent and evaporation todryness. The base used to prepare the salts may be organic, e.g. sodiummethoxide or an amine, or inorganic. Furthermore, other salts which arenot pharmaceutically acceptable may be useful for the synthesis of theacid compounds or other, acceptable salts.

The acid chlorides and simply alkyl esters of the acid compounds of theinvention are prepared starting, for example, with the correspondingacids. Thus, the acid chlorides may be made by reaction of the acidswith thionyl chloride, oxalyl chloride and the like, and the esters byreaction of the acid chlorides with a lower alkanol.

The antimicrobial activity of the compounds is evaluated using avariation of the original agar-plate diffusion method of Vincent andVincent (e.g. see Vincent, J. G., and Vincent, Helen W., Proc. oc.Exptl. Biol. Med. 55:162-164, 1944, and Davis, B. D., and Mingioli, E.S., J. Bac. 66:129-136, 1953). Using this test, the compounds of theinvention have been found to have a broad spectrum of activity againstboth gram-positive and gram-negative microorganisms. The procedureprovides information on the amount of a compound required to givecomplete inhibition, partial inibition or no inhibition of microbialgrowth on agar plates. The microbial growth on each plate is readvisually, and minimal inhibitory concentrations are recorded.

The microorganisms used are: Staphylococcus aureus, Bacillus subtilus,Pseudomonas aeruginosa, Escherichi coli, Streptococcus sp. (strainsisolated from dental caries in rats or hamsters at the NationalInstitute of Dental Health and grown in PFY or APT agar), Asperigillusniger, Candida albicans, Mima polymorpha, Herellea vaginicola,Klebsiella pneumoniae and Streptococcus fecaelis.

These are selected representatives of various bacterial and fungalclasses and broad spectrum activity can be predicted as a result ofactivity against them. All of the compounds of the invention possessantimicrobial activity towards one or more of the above microorganisms.The compounds maintain high activity against the microorganisms eitherin the absence or presence of ten percent horse serum.

The invivo antimicrobial activity is determined against infectionsproduced by Streptococcus pyogenes C-203 and Staphylococcus aureus(Smith) or other bacterial species. The species used is determined bythe in vitro antimicrobial spectrum of the compound. Groups of five orten mice, 18-22 g., are infected intra-peritoneally with the testculture. Treatment consists of three oral injections one, six and 24hours after infection. All mice are observed for extended periods, e.g.for two weeks, and deaths recorded at daily intervals. Control groupsconsist of one infected, nontreated group and other infected groupsreceiving varying dosages of the reference standard.

The acute oral toxicity of the compounds of the invention generally ismoderate to low compared with the effective oral dose, and they have agood to excellent therapeutic ratio.

The compounds of the invention may be formulated by incorporating theminto conventional pharmaceutical carrier materials, either organic orinorganic, which are suitable for oral or intraperitoneal application.For in vitro or topical use, simple aqueous solutions or suspensions aremost conveniently employed. For this purpose, concentrations of theorder of 100 parts per million up to about 5 parts per thousand aresuitable, and the formulation is used by immersing the object to betreated therein, or by local application to an infected area. The amountof compound to be used for treatment of a microbial infection will be aneffective amount less than a toxic amount. The amount to be administeredto a subject and route of administration to control an infection willdepend on the species of organism, the sex, weight, physical conditionof the subject, the locus of the infection, and many other factors, butthis judgment is well within the skill of the art. Usually the amountwill be less than 100 mg/kg per dose. Conveniently the oral treatment isadministered in the form of the usual pharmaceutical preparation such ascapsules, tablets, emulsions, solutions, suppositories and the like.Excipients, fillers, coatings, etc. are employed with tablets orcapsules, as is well known in the art.

It is often advantageous to combine the compounds of this invention withother antimicrobial compounds such as coccidiostats, anthelmintics,antifungals, antibiotics, steroids or antibacterial agents, or tocombine more than one compound described herein in a single composition.

Certain of the compounds are also active antiparasitics as shown byactivity in laboratory tests versus the protozoan Trichomonas sp. Inview of the outstanding antimicrobial activity of the compounds, theywould also be expected to be effective growth promoters in variousanimals and bird species.

The following examples are given for the purpose of illustrating theprocedures useful for preparing compounds of the invention, but are notintended to limit the scope of the invention. The melting points areuncorrected, and the temperatures are in degrees Centigrade.

EXAMPLE 1

Step A. A mixture of 10 g. (0.039 mole) of ethyl4-(4-hydroxyphenyl)phenylacetate, 7.8 g. (0.039 mole) ofα-bromoacetophenone and 11 g. (0.8 mole) of potassium carbonate in 250ml. of benzene is heated at its reflux temperature for about six days.The mixture is washed with water, twice with 100 ml. of 10 percentsodium hydroxide, then 100 ml. of 6 N hydrochloric acid and dried overcalcium sulfate. The solvent is evaporated to provide a residue which istriturated with hexane. Recrystallization of the solid product from anethyl acetate-hexane mixture providesα-4-[4-(carboethoxymethyl)phenoxy]acetophenone. Structural assignment isconfirmed by infrared and nuclear magnetic resonance spectral analysis.

Step. B. A mixture of 5.9 g. of acetophenone product from step A and 60g. of polyphosphoric acid is heated at 70° to 80° C. for 1.5 hours. Thinlayer chromatographic analysis indicates reaction is complete. Themixture is poured in 600 ml. of water and stirred, then extracted withchloroform. The extracts are dried over magnesium sulfate, thenevaporated to provide3-phenyl-5-[(4-carboethoxymethyl)phenyl]benzofuran. Structuralassignment is confirmed by infrared and nuclear magnetic resonancespectral analysis.

Step C. A mixture of the benzofuran product from step B, 50 ml. of 10percent sodium hydroxide solution and 100 ml. of ethanol is heated on asteam bath for two hours. The ethanol is evaporated and the residualsolution is acidified with 6 N hydrochloric acid. The product graduallycrystallizes and is recrystallized from aqueous ethanol to give3-phenyl-5-[(4-carboxymethyl)phenyl]benzofuran. Structural assignment isconfirmed by infrared and nuclear magnetic resonance spectral analysis.

Step D. A solution of 3.1 g. of3-phenyl-5-[(4-carboxymethyl)phenyl]benzofuran and 2 g. of dinitrogentetraoxide in 200 ml. of dichloromethane is stirred for about 16 hoursat about 20° C. The solvent is evaporated, and the residue is elutedfrom silica gel with chloroform. The product is obtained as a yellowsolid and recrystallized from a benzene-hexane mixture to provide2-nitro-3-phenyl-5-[(4-carboxymethyl)phenyl]benzofuran, m.p. 194°-197°C. This compound can also be named as4-(2-nitro-3-phenylbenzofuran-5-yl)phenylacetic acid.

    ______________________________________                                        Analysis:        % C       % H     % N                                        ______________________________________                                        Calculated for C.sub.22 H.sub.15 NO.sub.5 :                                                    70.8;     4.0;    3.7                                        Found:           70.1;     3.9;    3.8.                                       ______________________________________                                    

Step E. To a solution of 4 g. (0.0106 mole) of4-(2-nitro-3-phenylbenzofuran-5-yl)phenylacetic acid in 200 ml. ofbenzene at 5° C. is added slowly 4.1 g. (0.032 mole) of oxalyl chloridein 10 ml. of benzene. The reaction is stirred for 30 minutes whilewarming to about 20° C., then heated at reflux for three hours.Evaporation to dryness provides a residue which forms yellow solid4-(2-nitro-3-phenylbenzofuran-5-yl)phenylacetyl chloride when trituratedwith a hexane-benzene mixture.

Step F. To a solution of 2 g. (0.0051 mole) of sodium azide in 5 ml. ofwater and 5 ml. of acetone at 5° C. is slowly added the product of stepE in 50 ml. of acetone. Stirring is continued for two hours, after whichthe mixture is poured into 300 ml. of ice water. The solution isextracted thrice with 200 ml. portions of toluene. The toluene layersare dried, then heated at reflux for four hours. Evaporation provides4-(2-nitro-3-phenylbenzofuran-5-yl)phenylmethyl isocyanate.

Step G. The residue from step F is dissolved in 100 ml. ofdichloromethane, the solution is cooled to 5° C. and ammonia is bubbledin for 10 minutes. Cooling provides a yellow solid which is separated byfiltration to provide3-phenyl-5-[4-(ureidomethyl)phenyl]-2-nitrobenzofuran, m.p. 215°-216° C.

    ______________________________________                                        Analysis:        % C       % H      % N                                       ______________________________________                                        Calculated for C.sub.22 H.sub.17 N.sub.3 O.sub.4 :                                             68.2;     4.4;     10.8                                      Found:           68.1;     4.5;     10.8.                                     ______________________________________                                    

EXAMPLE 2

A solution of 2 g. (0.00536 mole) of4-(2-nitro-3-phenylbenzofuran-5-yl)phenylacetic acid (the product ofstep D of Example 1 hereof) in 100 ml. of tetrahydrofuran is cooled to0° C. and 20 ml. of a borane solution in tetrahydrofuran is added whileunder a nitrogen atmosphere over 10 minutes. After warming to 20° C. themixture is stirred for 16 hours. The solution is cooled to 0° C., 50 ml.of 1:1 water-tetrahydrofuran mixture and 15 ml. of 3 N sulfuric acid areeach added slowly and the mixture is stirred at 20° C. for 45 minutes.Evaporation provides a residue which crystallizes when triturated withhexane. Chromatography through silica gel in chloroform, eluting withchloroform, provides5-[4-(2-hydroxyethyl)phenyl]-2-nitro-3-phenylbenzofuran, m.p. 86°-87° C.

    ______________________________________                                        Analysis:        % C       % H     % N                                        ______________________________________                                        Calculated for C.sub.23 H.sub.17 NO.sub.4 :                                                    73.5;     4.77;   3.9                                        Found:           73.9;     5.1;    3.5.                                       ______________________________________                                    

EXAMPLE 3

Step A. A mixture of 137 g. (0.55 mole) of 2-bromo-4-phenylphenol, 109g. (0.55 mole) of α-bromoacetophenone and 75 g. of sodium carbonate in1.5 liters of acetone is heated at its reflux temperature for six days,filtered, then evaporated. The white residue is recrystallized from abenzene-hexane mixture to provide white needles ofα-(2-bromo-4-phenylphenoxy)acetophenone, m.p. 93°-95° C.

Step B. A mixture of 156 g. of the product of step A and 1 kg. ofpolyphosphoric acid is heated at 100° C. for seven days. The reactionmixture is poured into 5 liters of water and stirred, then extractedwith 2 liters of chloroform. The dried extracts are treated withdecolorizing charcoal, then evaporated. The residue is chromatographedon silica gel, eluting with carbon tetrachloride. The residue istriturated with hexane to provide 7-bromo-3,5-diphenylbenzofuran as apale yellow solid. The structural assignment is supported by infraredand nuclear magnetic resonance spectral analysis.

Step C. A mixture of 64 g. (0.18 mole) of the product of step B, 17.8 g.(0.2 mole) of cuprous cyanide and 35 ml. of pyridine is heated under anitrogen atmosphere at 150° to 160° C. for one day. The mixture ispoured into 1 liter of 3 N hydrochloric acid, extracted with 1 liter ofdichloromethane, and the extracts are dried. Evaporation provides aresidue which is chromatographed on silica gel, eluting withdichloromethane, to provide 7-cyano-3,5-diphenylbenzofuran as a paleyellow solid. The structural assignment is supported by infrared andnuclear magnetic resonance spectral analysis.

Step D. A mixture containing 30 g. (0.10 mole) of the product of step C,14.5 g. (0.22 mole) of 85 percent potassium hydroxide, 400 ml. ofethanol and 50 ml. of water is heated at its reflux temperature for 16hours, cooled and filtered. The product is washed with ethanol,suspended in water and acidified with 6 N hydrochloric acid. The mixtureis heated on a steam bath for one hour, cooled and filtered.Recrystallization from ethanol provides3,5-diphenylbenzofuran-7-carboxylic acid as a white solid.

Step E. A solution of 4.0 g. (0.013 mole) of the product of step D in 50ml. of dioxane is treated with 2.4 g. of bromine in 450 ml. ofchloroform, and the mixture is heated at its reflux temperatureovernight. The solution is cooled, washed with water, dried and thenevaporated. The residue is triturated with hexane to provide2-bromo-3,5-diphenylbenzofuran-7-carboxylic acid as a white solid, m.p.232°-236° C.

Step F. A solution of 6 g. (0.018 mole) of the product of step E in hotacetic acid is treated with 6 ml. of 70 percent nitric acid while thesolution is maintained at about 80° C. Sodium nitrite (2.7 g., 2equivalents) is added gradually, and the mixture is heated on a steambath for 45 minutes. The mixture is then poured into 500 ml. of water.The solid is filtered, recrystallized twice from acetone, then from anethyl acetate-hexane mixture to provide yellow crystals of3,5-diphenyl-2-nitrobenzofuran-7-carboxylic acid, m.p. 207°-209° C.

    ______________________________________                                        Analysis:        % C       % H     % N                                        ______________________________________                                        Calculated for C.sub.21 H.sub.13 NO.sub.5 :                                                    70.2;     3.6;    3.9                                        Found:           69.8;     3.6;    3.7.                                       ______________________________________                                    

EXAMPLE 4

Step A. A mixture of 71.7 g. (0.40 mole) of 4-(4-bromophenyl)phenol,79.1 g. (0.40 mole) of α-bromoacetophenone and 74 g. (0.7 mole) ofsodium carbonate in one liter of acetone is heated at its refluxtemperature for three days. Filtration and evaporation provides aresidue which is triturated with hexane, filtered and recrystallizedfrom ethanol. The product is white needles ofα-[4-(4-bromophenyl)phenoxy]acetophenone. Its structural assignment issupported by infrared and nuclear magnetic resonance spectral analysis.

Step B. A mixture of 72 g. of the product of step A and 700 g. ofpolyphosphoric acid is heated at 100° C. for three days, poured into 1.5liters of water and stirred. The mixture is extracted with chloroform (1liter), the extracts dried, then evaporated. The residue is dissolved inbenzene, and hexane is added to precipitate white solid which is removedby filtration. The filtrate is evaporated and the residue trituratedwith hexane to provide 5-(4-bromophenyl)-3-phenylbenzofuran.

Step C. A mixture of 21 g. of the product of step B, 12 g. of cuprouscyanide and 25 ml. of pyridine is heated at 150°-160° C. under anitrogen atmosphere for 24 hours, then poured into 200 ml. of 3 Nhydrochloric acid and stirred. Dichloromethane (150 ml.) is added, themixture is filtered, the organic layer is separated, washed with waterand dried. Evaporation provides a residue which is purified by elutingthrough a silica gel column with carbon tetrachloride to provide, afterevaporation of the solvent, 5-(4-cyanophenyl)-3-phenylbenzofuran.

Step D. A mixture of 10.2 g (0.034 mole) of the product of step C, 3.6g. (0.068 mole) of 85 percent potassium hydroxide, 20 ml. of water and200 ml. of ethanol is heated at its reflux temperature for three days,evaporated, then acidified with 6 N hydrochloric acid. The solidobtained is recrystallized from benzene to provide4-(3-phenylbenzofuran-5-yl)benzoic acid as a white solid. The structuralassignment is supported by infrared and nuclear magnetic resonanceanalysis.

Step E. A solution of 3.1 g. (0.01 mole) of the product of step D and 2g. of dinitrogen tetraoxide in 250 ml. of chloroform is stirred at about20° C. for about 16 hours. Evaporation of the mixture provides a residuewhich is dissolved in 10 percent sodium hydroxide solution, thenacidified with hydrochloric acid. The precipitate is collected byfiltration, dissolved in a chloroform/ethanol mixture andchromatographed on silica gel, eluting with chloroform. The solidobtained is recrystallized twice from a mixture of water andN,N-dimethylformamide to provide yellow crystals of4-(2-nitro-3-phenylbenzofuran-5-yl)benzoic acid, m.p. 259°-261° C.

    ______________________________________                                        Analysis:        % C       % H     % N                                        ______________________________________                                        Calculated for C.sub.21 H.sub.13 NO.sub.5 :                                                    70.2;     3.6;    3.9                                        Found:           69.9;     3.8;    4.0.                                       ______________________________________                                    

EXAMPLE 5

Step A. A solution of 75 g. (0.441 mole) of 4-hydroxybiphenyl, 50 g. ofsodium carbonate and 100 g. (0.36 mole) of α-bromo-4'-bromoacetophenoneis heated at its reflux temperature for about 6 hours, stirred at 20° C.for one day, diluted with 500 ml. of acetone and filtered hot. Aftercooling, the solid is collected by filtration to provideα-(4'-phenylphenoxy)-4-bromoacetophenone, m.p. 131°-133° C.

    ______________________________________                                        Analysis:          % C         % H                                            ______________________________________                                        Calculated for C.sub.20 H.sub.15 BrO.sub.2 :                                                     65.4;       4.1                                            Found:             65.9;       4.2.                                           ______________________________________                                    

Step B. A mixture of 86.3 g. of the product of step A and 800 g. ofpolyphosphoric acid is heated at 120° C. for about 18.5 hours, pouredinto ice water, then extracted with diethyl ether. The extracts arewashed with saturated sodium chloride solution and dried. The solidobtained is recrystallized from hexane to provide3-(4-bromophenyl)-5-phenylbenzofuran, m.p. 90°-92° C.

    ______________________________________                                        Analysis:         % C          % H                                            ______________________________________                                        Calculated for C.sub.20 H.sub.13 BrO:                                                           68.8;        3.4                                            Found:            68.8;        3.6.                                           ______________________________________                                    

Step C. A mixture of 58 g. of the product of step B, 17 g. of cuprouscyanide and 14 ml. of pyridine is heated at 200° C. for about fourhours, then poured into 50 g. of ferric chloride, 60 ml. of 6 Nhydrochloric acid and ice. Extraction with diethyl ether is followed bywashing of the extracts with saturated sodium chloride solution anddrying. Evaporation gives a residue which is chromatographed on silicagel, eluting with carbon tetrachloride, then a dichloromethane-carbontetrachloride mixture to provide 3-(4-cyanophenyl)-5-phenylbenzofuran.

Step D. A mixture of 25.1 g. of the product of Step C, 8.0 g. of sodiumhydroxide, 40 ml. of water and 40 ml. of ethanol is heated at its refluxtemperature for 16 hours, acidified and the solid collected byfiltration. Recrystallization from aqueous ethanol provides4-(5-phenylbenzofuran-3-yl)benzoic acid, m.p. 245°-248° C.

    ______________________________________                                        Analysis:         % C          % H                                            ______________________________________                                        Calculated for C.sub.21 H.sub.14 O.sub.3 :                                                      80.2;        4.5                                            Found:            80.1;        4.5.                                           ______________________________________                                    

Step E. A mixture of 3.2 g. of the product of step D, 2 g. of dinitrogentetraoxide, 1 ml. of acetic acid and 200 ml. of dichloromethane isstirred at 20° C. for 16 hours, washed with water and evaporated. Theresidue is treated with cold 5 percent sodium hydroxide solution, thenacidified with 6 N hydrochloric acid. The solid residue is separated andrecrystallized from N,N-dimethylformamide to provide4-(2-nitro-5-phenylbenzofuran-5-yl)benzoic acid, m.p. 235°-249° C.

    ______________________________________                                        Analysis:        % C       % H     % N                                        ______________________________________                                        Calculated for C.sub.21 H.sub.13 NO.sub.5 :                                                    70.2;     3.6;    3.9                                        Found:           70.1;     3.6;    3.7.                                       ______________________________________                                    

EXAMPLE 6

Step A. To a solution of 0.25 mole of sodium ethoxide is added 64 g.(0.25 mole) of ethyl 4-(4-hydroxyphenyl)phenylacetate. After stirringtwo hours the solution is evaporated, benzene is added, and the solutionis further evaporated. The residue is dissolved in 800 ml. of benzene,0.25 mole of ethyl α-chloroacetoacetate is added, and the mixture isstirred at room temperature, then heated at its reflux temperature for16 hours and filtered hot. Evaporation provides a residue which isdissolved in carbon tetrachloride and filtered through silica gel. Thisintermediate is treated with concentrated sulfuric acid at 0° C. Afterstirring one hour, ice is added and the mixture is extracted withbenzene. The benzene layer is dried, then evaporated. The residue isrecrystallized from a dichloromethanehexane mixture, then carbontetrachloride, to provide ethyl 4-(2-ethoxycarbonyl3-methylbenzofuran-5-yl)phenylacetate, m.p. 110°-112° C.

    ______________________________________                                        Analysis:         % C          % H                                            ______________________________________                                        Calculated for C.sub.22 H.sub.22 O.sub.5 :                                                      72.1;        6.05                                           Found:            72.1;        6.1.                                           ______________________________________                                    

Step B. A solution of 17 g. of the product of step A in 100 ml. ofacetic acid with 35 ml. of 48 percent hydrobromic acid is heated atreflux for three hours, then poured into ice water. This mixture isextracted into dichloromethane, and the extracts are dried to provide4-(3-methylbenzofuran-5-yl)phenylacetic acid. This intermediate isesterified by heating with a trace of sulfuric acid in ethanol. Theproduct is purified by chromatography on silica gel, eluting with 20percent dichloromethane in carbon tetrachloride to provide ethyl4-(3-methylbenzofuran-5-yl)phenylacetate.

Step C. To a solution of 2.8 g. of the product of step B in 50 ml. ofbenzene is added 2.7 g. of iodine and 2.4 g. of mercuric oxide followedby stirring and heating at 60°-65° C. for about three days. The mixtureis cooled and evaporated, and the residue is chromatographed on silicagel, eluting with a carbon tetrachloride-dichloromethane mixture, toprovide ethyl 4-(2-iodo-3-methylbenzofuran-5-yl)phenylacetate. To thisintermediate is added dichloromethane, then dinitrogen tetraoxide. Afterone hour the mixture is washed with water, then with sodium bisulfitesolution and dried. Evaporation provides a residue which isrecrystallized from a dichloromethane-hexane mixture to yield ethyl4-(3-methyl-2-nitrobenzofuran-5-yl)phenylacetate.

Step D. A solution of 1.5 g. of the product of step C in 25 ml. ofacetic acid and 10 ml. of 6 N hydrochloric acid is heated at its refluxtemperature for 45 minutes then poured into ice water. The precipitateis collected and recrystallized from an ethanol-N,N-dimethylformamidemixture to provide 4-(3-methyl-2-nitrobenzofuran-5-yl)phenylacetic acid,m.p. 229°-230° C.

    ______________________________________                                        Analysis:        % C       % H     % N                                        ______________________________________                                        Calculated for C.sub.17 H.sub.13 NO.sub.5 :                                                    65.6;     4.2;    4.5                                        Found:           65.9;     4.2;    4.6.                                       ______________________________________                                    

What is claimed is:
 1. A compound of the formula ##STR7## wherein Z ishydrogen or alkyl of one to four carbon atoms, A is methyl or ethyl andB is hydrogen or ethyl carboxylate.